The long-term objective of this proposal is to understand the role of the YAP oncogene in the initiation of pancreatic ductal adenocarcinoma (PDA). PDA has the highest mortality rate of all major cancers; 74% of patients die within the first year of diagnosis and only 6% survive more than 5 years. Surgical removal is the only effective cure but due to the lack of specific symptoms, the majority of patients are not diagnosed until the tumors have become inoperable. Hippo signaling is a recently discovered, well-conserved developmental signaling pathway, consisting of a core kinase cascade that phosphorylates and inactivates the Yes Associated Protein (YAP), its downstream effector. YAP levels and activity have been reported to be high in various human cancers, and it is becoming recognized as an important human oncogene. Although recently it has been reported that Hippo signaling has crucial roles in pancreas development, its role in PDA has not been well investigated. The proposed research aims to determine if YAP is required or sufficient for the formation of acinar-to-ductal metaplasia (ADM), the earliest precursor lesions of PDA, as well as whether YAP oncogene can synergize with oncogenic Kras (KrasG12D) during the initiation of PDA. Genetically engineered mouse models of PDA have long been powerful tools to study the mechanisms governing initiation and progression of PDA. In particular, the oncogenic KrasG12D-driven PDA mouse model, where Kras (a small GTPase) is activated in the pancreatic epithelia, faithfully recapitulates all of the events in human PDA. The proposed research will combine well-characterized KrasG12D-driven mouse models with loss-of-function and gain-of- function alleles of YAP to investigate YAP's role in the initiation events of PDA, which will provide us with new avenues of research for early detection and treatment.